Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti-cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress.
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PMID:The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response. 2476 52

Upregulation of heme oxygenase 1 (HO-1) by carbon monoxide (CO) delivered by CO-releasing molecules (CORMs) may be utilized as a therapeutic intervention for neurodegenerative diseases. This study was to delineate the two putative anti-oxidant response elements (AREs) in modulating HO-1 gene by participating with its promoter elements in rat brain astrocytes (RBA-1). CORM-2-induced HO-1 expression was mediated through superoxide, p38 mitogen-activated protein kinase(MAPK), extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), protein tyrosine kinase 2 (Pyk2), platelet-derived growth factor receptor (PDGFR), and phosphatidylinositol 3'-kinase (PI3K/Akt), revealed by the pharmacological inhibitors or knockdown of these signaling molecules. CORM-2-enhanced HO-1 promoter activity was inhibited by co-transfection with small interfering RNA (siRNA) of c-Jun, specificity protein 1 (Sp1), or nuclear factor-erythroid 2-related factor 2 (Nrf2). Immunoprecipitation assay showed that CORM-2 increased the association of nuclear Nrf2 with Sp1 and c-Jun. Furthermore, chromatin immunoprecipitation (ChIP) assay confirmed that Nrf2, Sp1, and c-Jun are associated with the proximal ARE binding site on HO-1 promoter, suggesting that Nrf2/Sp1/c-Jun cooperations are key transcription factors modulating HO-1 expression. Mechanistically, CORM-2-induced ARE promoter activity was reduced by the inhibitors of reactive oxygen species (ROS), p38 MAPK, Pyk2, MAPK/ERK kinases 1 and 2 (MEK1/2), PDGFR, and PI3K/Akt or the siRNAs of c-Jun, SP1, and Nrf2. These findings suggested that CORM-2 increases formation of c-Jun, Sp1, and Nrf2 complex and binding with ARE1 binding site, which is mediated through both ROS/p38 MAPK and Pyk2-dependent PDGFR/PI3K/Akt/Erk1/2 pathways, resulting in HO-1 expression in RBA-1 cells.
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PMID:CO Induces Nrf2-Dependent Heme Oxygenase-1 Transcription by Cooperating with Sp1 and c-Jun in Rat Brain Astrocytes. 2514 34